Although no longer used commercially, polychlorinated biphenyls (PCBs) persist in the environment and exposure is still significant for some human populations. Meanwhile, the environmental levels of polybrominated diphenyl ether flame retardants (PBDEs) are increasing exponentially. PBDEs are chemically similar to PCBs, making the potential for additive effects a concern. The adverse neurodevelopmental effects of PCBs/PBDEs are becoming more widely recognized, but need to be better defined. Animals and children exposed to PCBs exhibit deficits on several learning tasks that require inhibitory control, but the underlying processes responsible for these deficits are not well understood. Closer evaluation of the specific aspects of inhibitory control impaired by developmental PCB exposure and the neurochemical mechanisms underlying these effects will lead to a better overall understanding of the cognitive deficits associated with PCB exposure. The proposed studies will be conducted in parallel with ongoing studies in the primary sponsor's laboratory which focus on understanding the cognitive effects of PCBs/PBDEs. The specific aims of the current proposal are 1) to use a rodent model to assess the effects of developmental exposure to PCBs, PBDEs or both on 3 distinct aspects of response inhibition - the ability to inhibit unnecessary or premature responding, the ability to stop a response once it has been initiated, and the ability to tolerate a delay in reinforcement; 2) to use systemic and direct intracranial drug challenges to gain a better understanding of the role of perturbations in dopamine and norepinephrine neurotransmission in mediating the effects of PCB/PBDE exposure on these specific aspects of response inhibition; and 3) to use western blot analysis to quantify expression of catecholamine-related transporters and receptors in specific brain regions important for response inhibition in order to further define the synaptic changes that occur with developmental PCB/PBDE exposure. The results will be important in estimating risk to human populations that have ongoing exposure to these ubiquitous environmental contaminants. Because similar problems with inhibitory control are seen in children with attention deficit hyperactivity disorder, the results may also contribute to a better understanding of this common childhood disorder.